A. Sandrelli

In vitro pharmacological purging of human bone marrow is enhanced by the use of lonidamine

Lonidamine (LND), previously reported as a useful antitumor substance in combination with physical or chemical agents, has been studied for its capacity in increasing pharmacological elimination in vitro of residual tumor cells from human bone marrow. Different drugs were tested in association with LND against mixtures of human bone marrow and a tumor cell line, clonogenic human leukemic blast progenitors, and normal human bone marrow precursors. The results demonstrated that LND increased the efficacy of anthracycline derivatives (Adriamycin, Mitoxantrone) both on the tumor cell line and on the leukemic blast progenitors, while VP-16 or ASTA-Z 7654 was not affected by the same substance. The toxicity on normal stem cells reflected that of each drug and was not modified by the addition of LND. While a consistent dose-dependent CFU-GM reduction was observed immediately after treatment with the different drugs, a complete recovery was reached after 7 and 14 days of long-term marrow cultures. Because of the low toxicity and the efficacy demonstrated in association with certain agents in increasing tumor cell elimination in vitro, LND could play an important role in in vitro purging prior to autologous bone marrow transplantation.

Acute myelogenous leukemia in first relapse treated with two consecutive autologous bone marrow transplantations: a pilot study

The feasibility and the antileukemic activity of a double sequential autograft has been evaluated in 3 patients affected by AML in first hematological relapse. Bone marrow collection and cryopreservation was performed twice: during first complete remission (CR) and during second CR. At the time of relapse patients underwent first ABMT with BAVC preparative regimen achieving a second CR without any remarkable complications. After 4, 5 and 4 months respectively a second ABMT was performed with a different preparative regimen, consisting of cyclophosphamide and fractionated total body irradiation (Cy + F‐TBI). A delay in platelet recovery was observed after the second procedure as compared to the first, while neutrophils recovery was comparable. 1 patient died in CR (on day +91 after second ABMT) of interstitial pneumonitis. 2 patients are alive and well without evidence of disease after 46 and 53 months of unmaintained second CR. This experience shows the high antieleukemic potential of treatment with a double sequential autograft; 2 relapsed patients in fact are long‐term survivors with a second CR longer than the first.

Autologous Bone Marrow Transplantation (ABMT) for Patients with Chronic Granulocytic Leukemia (CGL) in Blastic Phase (BP)

Autologous hemopoietic stem cell infusion after high dose chemo/radiotherapy performed in BP of CGL is able to reinduce II CP in 90% of patients; however the median survival does not last more than 6 months. This report concerns 5 patients with Phl positive CGL in BP treated with BAVC regimen followed by hemopoietic stem cells reinfusion. An intensification program of cyclic chemotherapy has been applied after ABMT with the aim to prolong the survival of these patients. Since 1980 the majority of CGL patients seen at the Institute of Hematology of Rome were subjected to collection and cryopreservation of hemopoietic stem cells from bone marrow (BM) or peripheral blood (PB). Details of the methods have been described elsewhere (1,2). Of the 5 patients presented in this report 4 received stem cells collected from PB and 1 from BM. Four patients were males, median age was 39 years (range 29–41). Therapy during CP consisted of hydroxyurea; no splenectomy had been performed in any patient. Type of transformation was myeloid in 4 cases and mixed in one. BAVC conditioning regimen consisted of BCNU 800 mg/mq day 1; AMSA 150 mg/mq/day on days2–4; VP-16 150 mg/mq/day days 2–4; CA 300 mg/mq/day c.i. days 2–4. Stem cells were reinfused 24 hours after last dose chemotherapy with a median of 11×108(range 3–21) nucleated cells/kg body weight. After complete hematological reconstitution (25–30 days) from autologous infusion an intensification program of cyclic chemotherapy was begun consisting of 3 courses of L-VAMP (VCR 1.5 mg/mq i.v. hour 0,MTX 200mg/mq c.i. hours 1–3,CA 500 mg/mq c.i. hours 3–7, ASNASI 5000 U/mq i.m. hour 24,PDN 40 mg/mq/day days 1–5);3 courses of DAT (DNR 60 mg/mq i.v. day l,CA 60 to 150 mg/mq/8 hours s.c. days 1–5,6-TG 70 mg/mq/8 hours p.o. days 1–5) and 3 courses of HiDAC (CA 1 g/mq/12 hours c.i. in 3 hours on hour 0,12; ASNASI 6000 U/mq i.v. on hour 18).

Pharmacological purging of syngeneic bone marrow ex vivo : effect of treatment with doxorubicin and lonidamine on normal and leukaemic cells of DBA/2 mice

The in vivo effect of in vitro treatment with doxorubicin plus lonidamine on normal and leukaemic cells was investigated in a mouse model of syngeneic bone marrow transplantation. Different numbers of L5178Y tumour cells or normal bone marrow cells alone, or mixtures of bone marrow and leukaemic cells were incubated with doxorubicin (0.25, 0.5, 0.75, 1 microgram/ml) and/or lonidamine (50 micrograms/ml) and reinfused in DBA/2 mice. Lonidamine potentiated the cytotoxic effect of doxorubicin dependent on doxorubicin dosage and tumour cell concentration. Survival after injection of 10(4) in vitro-treated tumour cells was 42% for doxorubicin 0.75 micrograms/ml alone versus 100% for the combination with lonidamine and 50% for doxorubicin 1 microgram/ml alone versus 100% combination. Reinfusion of normal bone marrow incubated with doxorubicin alone or in combination with lonidamine in lethally irradiated mice did not occur in 12-14% of mice injected, indicating that the repopulating ability of stem cells was spared. These data suggest the potential usefulness of lonidamine in ex vivo purging of bone marrow before autologous bone marrow transplants in haemopoietic malignancies.

In Vitro and In Vivo Inhibitory Effects of Interferon α 2b on CML Granuloerythroid Precursors

Chronic myelogenous leukemia (CML) is a clonal hemopathy in which malignant transformation probably occurs in an early hemopoietic precursor cell. The initial chronic phase is easily treated by chemotherapy, but the fatal course of the disease rapidly evolves into the acute phase that is very difficult to control with conventional drugs.

Autologous bone marrow transplantation for patients with acute myelogenous leukemia in complete remission.

Acute myeloid leukemia (AML) patients in hematological relapse have minimal chances of long-term survival. Allogeneic bone marrow transplantation (BMT) gives an opportunity for cure in such patients, but a t the expense of high mortality due to graft-versus-host disease and opportunistic infections. Furthermore, only 3 5 4 0 % of all patients who are potential candidates for BMT have related HLA-matched donors. Different approaches, therefore, have been looked for in treating patients with relapsed AML. Intensive myeloablative antileukemic therapy followed by the infusion of cryopreserved remission bone marrow (autologous bone marrow transplantation, ABMT) has been successfully tested with results that, through slightly inferior to BMT, compare favorably with the best results of conventional therapy for relapsed AML.’ Indeed, most relapsing patients are reinduced into complete remission (CR) by ABMT, though less than 5% are long-term survivors. The higher relapse rate observed in ABMT patients than in BMT patients may be due either to the presence of undetected leukemic blasts in the cryopreserved remission bone marrow or to inadequate antileukemic effect of the conditioning regimen itself. Our observation that a few relapsed AML patients, induced into C R by ABMT and consolidated by a second myeloablative treatment with autologous marrow rescue, enjoy a long-term C R seems to favour the latter hypothesis.’ On the basis both of these considerations and of the preceding experience with BMT in AML patients in first remission, high-dose cytoreductive therapy followed by ABMT has been employed in earlier phases of the disease, i.e. as a very intensive consolidation treatment after achieving CR.3 At our Institute, a 4-drug conditioning regimen, BAVC (BCNU, AMSA, VP16, cytosine-arabinoside), followed by autologous marrow rescue, whose efficacy had been previously tested in AML patients in first relapse: has been employed in a trial open to AML patients in first or second CR.

High dose polichemotherapy with autologous bone marrow transplantation in recurrent medulloblastoma. A pilote study

Despite the rising survival rate, no therapeutic regimen available at present can cure recurrent medulloblastoma, and the late effects of the current treatments are largely unknown. Thus the management of medulloblastoma remains a perplexing problem.